Does metformin (biguanide oral hypoglycemic) affect vitamin B12 levels?

From the Guidelines

Metformin can affect vitamin B12 levels, and long-term use may be associated with biochemical vitamin B12 deficiency. The most recent and highest quality study, 1, suggests that long-term use of metformin may be associated with vitamin B12 deficiency, and periodic assessment of vitamin B12 level in those taking metformin chronically should be considered, especially in those with anemia or peripheral neuropathy. Key points to consider:

• Long-term metformin use can decrease vitamin B12 absorption in the ileum by interfering with calcium-dependent membrane action.
• The effect is dose-dependent, with higher doses and longer duration of treatment increasing the risk of deficiency.
• Approximately 10-30% of patients taking metformin chronically may develop vitamin B12 deficiency.
• Patients on metformin should have their vitamin B12 levels checked periodically, especially those on higher doses (>1500 mg daily) or who have been taking the medication for several years.
• If deficiency is detected or suspected, supplementation with vitamin B12 (typically 1000 mcg daily or 1000-2000 mcg weekly) is recommended.
• Symptoms of B12 deficiency include peripheral neuropathy, anemia, fatigue, and cognitive changes, which can be mistaken for diabetic neuropathy or other diabetes complications.
• Healthcare providers should consider routine B12 monitoring every 1-2 years for patients on long-term metformin therapy, particularly in elderly patients who are already at higher risk for B12 deficiency, as suggested by 1 and 1.

From the FDA Drug Label

In metformin hydrochloride tablets clinical trials of 29-week duration, a decrease to subnormal levels of previously normal serum vitamin B 12 levels was observed in approximately 7% of patients Such decrease, possibly due to interference with B 12 absorption from the B 12-intrinsic factor complex, may be associated with anemia but appears to be rapidly reversible with discontinuation of metformin hydrochloride tablets or vitamin B 12 supplementation Certain individuals (those with inadequate vitamin B 12 or calcium intake or absorption) appear to be predisposed to developing subnormal vitamin B 12 levels. Measure hematologic parameters on an annual basis and vitamin B 12 at 2 to 3 year intervals in patients on metformin hydrochloride tablets and manage any abnormalities [see Adverse Reactions ( 6.1) ].

Metformin can affect vitamin B12 levels. A decrease to subnormal levels of previously normal serum vitamin B12 levels was observed in approximately 7% of patients. This decrease may be due to interference with B12 absorption and can be associated with anemia. However, it appears to be rapidly reversible with discontinuation of metformin or vitamin B12 supplementation. Patients on metformin should have their hematologic parameters measured annually and vitamin B12 levels checked every 2 to 3 years, and any abnormalities should be managed accordingly 2, 2, 2.

From the Research

Metformin and Vitamin B12 Levels

• Metformin use has been associated with lower vitamin B12 levels in patients with type 2 diabetes, with a significant mean reduction of 57 pmol/L 3.
• Long-term use of metformin has been linked to an increased risk of vitamin B12 deficiency, with a higher risk of deficiency observed with higher doses and longer treatment durations 4, 5.
• A meta-analysis of 31 studies found that metformin use was associated with a significantly higher risk of vitamin B12 deficiency (RR 2.09; 95% CI 1.49,2.93) and lower serum vitamin B12 concentrations (MD -63.70; 95% CI -74.35, -53.05] pM) 6.

Risk Factors for Vitamin B12 Deficiency

• Higher doses and longer durations of metformin treatment have been identified as risk factors for vitamin B12 deficiency 4, 5.
• Patient age and ethnicity may also be risk factors, although further research is needed to confirm this 5.
• Routine vitamin B12 screening is recommended, prioritizing higher-risk patients 5, 6.

Clinical Implications

• Vitamin B12 deficiency can lead to hematologic abnormalities, such as megaloblastic anemia, and neurologic symptoms, such as peripheral neuropathy 7, 6.
• Annual vitamin B12 assessment is recommended for diabetic patients taking metformin to monitor for deficiency and prevent related complications 6.
• Further research is needed to explore the associations between metformin use and anemia and neuropathy in patients with diabetes 6.